Atherosclerosis 192 (2007) 323–327 Angiotensin II increases expression and secretion of cathepsin F in cultured human monocyte-derived macrophages: An angiotensin II type 2 receptor-mediated effect Riia Kaakinen, Ken A. Lindstedt, Mia Sneck, Petri T. Kovanen, Katariina ¨ O¨ orni ∗ Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland Received 4 January 2006; received in revised form 7 July 2006; accepted 2 August 2006 Available online 11 September 2006 Abstract Increasing evidence suggests that cathepsins and angiotensin II (AngII) participate in atherosclerosis, particularly in remodeling of the extracellular matrix of the inflamed arterial intima. Here, we show that AngII induces mRNA expression of cathepsin F, a member of the cysteine protease family, in human monocyte-derived macrophages. AngII did not affect the amount of intracellular cathepsin F protein, but significantly enhanced its secretion by the treated cells. The stimulatory effect of AngII was mediated by the AngII type 2 (AT 2 ) receptor, as demonstrated by the ability of the AT 2 -receptor antagonist PD123319 to block the AngII-induced increase in cathepsin F secretion. Our present data demonstrate a novel proatherogenic role for AngII, namely its ability to enhance secretion of lysosomal cathepsin F by monocyte-derived macrophages. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Cathepsins; Proteolysis; RAS 1. Introduction Throughout the development and progression of atherosclerosis, proteolysis is involved in critical patho- logical processes including the initial steps of lipoprotein modification and accumulation as well as the later steps of plaque rupture due to degradation of intimal extracellular matrix. Many proteases have been shown to be expressed selectively in atherosclerotic lesions both in humans and in experimental animals [1–3], and when compared with normal arteries, the atherosclerotic lesions have been documented to possess increased elastase, collagenase, and gelatinase activities [4]. Cathepsins of the cysteine protease family have tradi- tionally been thought to play a major role in intracellular Abbreviations: AngII, angiotensin II; AT 1 -receptor, angiotensin II type 1 receptor; AT 2 -receptor, angiotensin II type 2 receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MMP, matrix metallopro- teinase ∗ Corresponding author. Tel.: +358 9 681 411; fax: +358 9 637 476. E-mail address: kati.oorni@wri.fi (K. ¨ O¨ orni). protein degradation and turnover in lysosomes [5]. However, accumulating evidence indicate that many cell types have the ability to secrete cathepsins. Thus, cultured monocyte- derived macrophages [2,6,7] and smooth muscle cells [1] and endothelial cells [8], when stimulated with proinflammatory cytokines, have been shown to secrete various cathepsins. On the basis of the above findings, a role in the degradation of the extracellular matrix has been assigned to the secreted cysteine proteases in the arterial intima [4]. Cathepsin F, a member of the cysteine protease family, is a potent endopeptidase, which shows very high activity towards peptide substrates [9]. The enzyme was recently shown to be present in atherosclerotic lesions, where it colocalizes with macrophages [2]. In addition, cultured human monocyte-derived macrophages were found to secrete cathepsin F. In the arterial intima, the protese may participate in the remodeling of the intimal extracellular matrix [10] and in the modification of lipoprotein particles during atheroge- nesis [2,11]. The relevance of angiotensin II (AngII) in the pathogenesis of atherosclerosis is well characterized [12–16]. Recently, the 0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2006.08.001